Opthalmic solution for artificial tears

ABSTRACT

An ophthalmic artificial tear solution is described for treating irritation and dryness of the eyes with a formulation that includes polyvinylpyrrolidone, a preservative such as benzalkonium chloride, glycerin and hydroxypropyl methylcellulose, wherein the composition is an aqueous solution having isotonic properties with respect to the eye. The ophthalmic solution of the invention is characterized as having a low viscosity, preferably less than 5 cps, and a low surface tension, preferably less than 40 dynes/cm, wherein wettability, retainability and comfort of the user are enhanced.

This is a continuation of application Ser. No. 08/380,931 filed on Jan.31, 1995 now U.S. Pat. No. 5,591,426.

BACKGROUND OF THE INVENTION

The present invention relates to ophthalmic compositions that relieveeye irritation or dryness and provide lubrication for the eyes. Moreparticularly, the invention relates to ophthalmic solutions thatfunction as artificial tears and can be used, as needed, for temporaryrelief of and protection against eye irritation.

Many people suffer from temporary or chronic eye conditions wherein theeye's tear system fails to provide adequate tear volume or tear filmstability to remove irritating environmental contaminants such as dust,pollen or the like. Where the tear film on ocular surfaces becomesdiscontinuous, the condition is often called "dry eye".

Such failures of the tear system result in significant personaldiscomfort, such as dry, itching, burning and irritating eyes. Treatmenttypically involves applying a slightly viscous solution in drop form tothe eyes to provide at least a temporary wetting before the solutionevaporates or is wiped away by operation of the eyelids. Since thesolution tends to be cleared from the eye rather quickly, frequentdosing is generally necessary.

A key element of an artificial tears solution is a polymer systemdesigned to mimic the action of mucin and or/lipids, which are theprincipal active natural components of tear fluid. The polymer systemselected for artificial tears acts as a wetting agent in the eye and isresponsible for contributing to tear film stability.

In addition to the active polymer system ingredients, a preservativesystem that is effective for maintaining solution sterility is typicallynecessary. Its purpose is to prevent bacteria and other organisms fromcontaminating the solution after its container has been opened and aninitial dose has been used. Such a preservative is a necessary componentof artificial tears where packaging is in other than single dose units.

An example of a prior artificial tears solution is described by Bapatlaet al in U.S. Pat. No. 4,120,949. Bapatla pointed out that earliercommercially available artificial tear solutions had been eitherexcessively viscous and, therefore, difficult to use or were so low inviscosity that the solution could not form a sufficiently long lastingfilm. Bapatla's artificial tear composition said to have a relativelylong film life, contains polyvinyl alcohol (0.1-10.0%), hydroxyethylcellulose (0.1-5.0%) and polyvinylpyrrolidone (0.1-20.0%). Bapatala'sExamples report viscosities ranging between 5 and 270 cps. However, allbut one are relatively high viscosities, in the 80-270 cps range.Surface tension of the solutions of the Examples ranged from between 33and 45 dynes/cm.

In a review article on surface interfacial and molecular aspects ofpolymer bioadhesion of soft tissues, Nikolaos A. Pappas and Pierre A.Buri Journal of Controlled Release, 2(1985) 257-275! quote A. J. KinlockJ. Mater. Sci. 15 (1980) (2141! as stating that bioadhesion is enhancedfor liquid adhesive materials characterized by zero or near zero contactangles and having relatively low viscosities. Tiffany et al, in "TearFilm Stability and Tear Surface Tension" Current Eye Research, Vol. 8,No. 5 (1989), finds a negative correlation between surface tension andbreak-up-time for tear film on the human eye. These works suggest thatlow surface tension may be a useful factor for artificial tears thatmust adhere readily to corneal surfaces.

A particularly useful wetting agent that does not unduly increase theviscosity of ophthalmic solutions is polyvinylpyrrolidone (PVP). PVP hasa number of other characteristics that makes it useful in combinationwith the various well known components in ophthalmic solutions.

Rankin, in U.S. Pat. No.3,920,810, notes that polyvinylpyrrolidone actsas a detoxicant, binding anti-toxins present in eye fluids and renderingthem harmless. PVP also acts to protect a treatment solution bypreventing its breakdown, through particle agglomeration. Additionally,PVP acts as a demulcent lubricant by means of a combination of adhesiveand lubricating properties that aid in the spreading of the viscoussolution.

Preferred preservatives utilized in ophthalmic solutions may includequaternary ammonium compounds, particularly benzalkonium chloride (BAK),as described by Hecht et al in U.S. Pat. No. 4,039,662. Although BAK isan effective preferred preservative, it is often limited inconcentration and, hence, usefulness because of some users' sensitivitythereto.

Blanco et al, in U.S. Pat. No. 4,029,817, teaches that quaternaryammonium compounds, e.g. benzalkonium chloride, when combined with adetoxifying amount of certain polymers, may be utilized in contact lenscleaning solutions at BAK concentration levels otherwise known to beirritating and potentially harmful. A list of suitable polymersincludes, among others, polyvinylpyrrolidone.

It would be desirable to provide a formulation that provides effectiverelief from dry and irritating eye conditions by means of componentsthat combine to provide good wetting and retainability in the eye whichformulation also includes a reliable preservative that is renderedsubstantially less irritating or non-irritating.

SUMMARY OF THE INVENTION

The present invention describes an eye drop formulation for relief fromirritation or dryness of the eyes which eye drop provides lubricationand moisturizing for the eyes.

The present invention provides an ophthalmic aqueous solution that isuseful as an artificial tear and comprises polyvinylpyrrolidone and aneffective ophthalmic preservative, such as benzalkonium chloride,wherein the PVP provides adhesion of the composition to cornealsurfaces, binds anti-toxins and complexes with BAK such that risk ofirritation to the user is reduced.

The formulation of the invention is of low surface tension, preferablybelow 40 dynes/cm, and of low viscosity, preferably below 5 cps. Saidcomposition further includes hydroxypropyl methylcellulose and glycerinto provide demulcent activity.

The composition may further include, as is well known, buffers, surfaceactive agents and salts, such that the solution is substantiallyisotonic.

A preferred artificial tear composition of the invention, consists of:

(1) polyvinylpyrrolidone, preferably in an amount of about 0.1-1.5% byweight of said solution;

(2) benzalkonium chloride, preferably in an amount of about 0.01-0.10%by weight;

(3) hydroxypropyl methylcellulose, preferably in an amount of about0.2-1.5% by weight of said solution; and

(4) glycerin, preferably in an amount of about 0.2-1.0% by weight ofsaid solution, wherein the composition is an aqueous solution havingisotonic properties.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is an ophthalmic solution that is principallycharacterized by low viscosity and low surface tension relative topreviously known solutions. Preferably, at 25° C., the viscosity is lessthan about 5 cps and surface tension is less than about 40 dynes/cm.Both of these characteristics are useful in promoting good wettabilityand spread, as well as good retention and stability on the eye, withoutsignificant discomfort of the user.

In addition, the ophthalmic solution of the invention includes glycerinand hydroxypropyl methylcellulose which act as humectants. Thehumectants enhance water retention in the eye and enhance moisturizingcapabilities of the solution. These identified materials also possesssignificant demulcent activity.

The key components of the formulation of the invention and preferredconcentration thereof comprise:

    ______________________________________    polyvinylpyrrolidone                        0.1-1.5%    benzalkonium chloride                        0.01-0.10%    hydroxypropyl methylcellulose                        0.2-1.5%    glycerin            0.2-1.0%    ______________________________________

In addition, conventional and well known buffers, salts and the like maybe included to form an isotonic, buffered system.

A key element of the ophthalmic artificial tear solution of theinvention is the combination of polyvinylpyrrolidone and benzalkoniumchloride. The PVP provides tear film stability and wetting of thecorneal surfaces and also allows the use of BAK in effectivepreservative concentrations in the solution.

The polyvinylpyrrolidone (PVP) used in the compositions of the inventionis a linear polymer of 1-vinyl-2-pyrrolidone groups, preferably having amolecular weight of about 35,000 to 51,000. Such materials are sold byISP Technologies, Inc. under the trademark PLASDONE™ K-29/32. It is tobe understood, however, that the invention is not limited to anyspecific PVP and that any equivalent PVP of pharmaceutical grade may beused.

The quaternary ammonium compound benzalkonium chloride is characterizedas a mixture of alkyldimethyl benzylammonium chlorides. It is employedin a preferable concentration of about 0.01% by weight of the solution.The preserved formula is intended for use in the eye in the absence of acontact lens, since the use of benzalkonium chloride with contact lensis contraindicated due to irritation potential.

The solution of the invention is useful by contact lens wearers. Sorbicacid or other suitable ophthalmic preservatives that are not irritatingto the eyes are used. Such a formula is also characterized by, at 25°C., very low viscosity (below 5 cps) and low surface tension (below 40dynes/cm).

The hydroxypropyl methylcellulose (HPMC) functions to provide a desiredlevel of viscosity and to provide demulcent activity. It ischaracterized as a mixed ether of cellulose containing a variableproportion of methoxyl and 2-hydroxypropoxyl groups and is purchasedfrom Dow Chemical under the trademark Methocel E 15 LV -Premium. It isto be understood that the invention is not limited to any specifichydroxypropyl methylcellulose and that any equivalent HPMC ofpharmaceutical grade may be used.

The ophthalmic solutions of this invention preferably contain a buffersystem to control pH. Any pharmaceutically acceptable buffer system maybe utilized. A preferred buffer system is provided by sodiumborate/boric acid in amounts necessary to produce a pH of about 6.0 to8.0. A preferred pH range is about 6.5-7.8 and a most preferred range isabout 7.1-7.5.

The ophthalmic solutions of this invention are isotonic with respect tothe fluids of the human eye. These solutions are characterized byosmolalities of 270-330 mOsm/kg. Osmolality of the solution of theinvention is adjusted by means of sodium chloride and potassiumchloride.

The formulation of the invention may include a number of additionalcomponents to provide various effects, as is well known in this field.For example the solution may include edetate disodium, which mayfunction as a co-preservative and chelating agent.

The following examples illustrate the invention without limiting itsscope. All percentages are by weight of the solution.

EXAMPLE 1

An aqueous solution of the invention is prepared, including thefollowing ingredients:

                  TABLE    ______________________________________    Polyvinylpyrrolidone                      1.00          mg/mL                                        0.100%    Benzalkonium Chloride, 50%                      0.20         mg/mL                                        0.020%    Hydroxypropylmethyl cellulose                      5.00         mg/mL                                        0.500%    Glycerin          2.00         mg/mL                                        0.200%    Edetate Disodium  0.30         mg/mL                                        0.030%    Boric Acid        3.00         mg/mL                                        0.300%    Sodium Borate     0.35         mg/mL                                        0.035%    Potassium Chloride                      3.50         mg/mL                                        0.350%    Sodium Chloride   4.00         mg/mL                                        0.400%    Purified Water    1.00         mL   to 100%    ______________________________________

The formulation is prepared by adding each of NaCl, KCl, Na Borate,Boric Acid, EDTA and HPMC (Type E15-LV Premium) to a volume of waterthat is 70-85% of the final batch volume, under agitation and initiallyheated to 80-90° C. Each component is allowed to dissolve or dispersebefore adding the next. With continued agitation, the batch is cooled to50° C. (±5° C.) and mixed for 20 minutes while cooling. Continuing toagitate, the PVP K-30, glycerin and BAK (50% solution) are eachsequentially dissolved or dispersed. The batch is cooled under agitationto 20° C. (±5° C.) for a minimum of 20 minutes. The pH is then adjustedto 7.1-7.5 using increments of either 1N NaOH or 1N HCl. The solution isbrought to final volume with 20-30° C. water and mixed for at least 15minutes. The BAK concentration is adjusted to a 95-110 ppm content.

EXAMPLE 2

Four samples of the formulation of Example 1 are prepared andcharacterized by viscosity and surface tension.

    ______________________________________                Viscosity  Surface Tension    Sample No.  (cps at 25° C.)                           (dynes/cm at 25° C.)    ______________________________________    1           2.1        35.2    2           2.1        33.8    3           2.1        33.4    4           2.1        33.1    ______________________________________

What is claimed:
 1. An ophthalmic solution useful as artificial tearsconsisting essentially of about 0.1 to 1.5% by weight ofpolyvinylprrolidone, sodium borate/boric acid, about 0.2 to 1.0% byweight of glycerin, and 0.01 to 0.10% by weight of an effectiveophthalmic preservative, wherein said solution is an aqueous solutionhaving isotonic properties with respect to the eye, whereby theosmolality has been adjusted with sodium chloride and potassiumchloride.
 2. The ophthalmic solution of claim 1 wherein said ophthalmicpreservative is benzalkonium chloride (BAK), sorbic Acid, chlorobutanol,disodium, ethylenediamine tetra-acetate, polyquaternium-1 oralkyltrimethylammonium bromide.
 3. The ophthalmic solution of claim 2,wherein the preservative is benzalkonium chloride or cetyltrimethylammonium bromide.
 4. The ophthalmic solution of claim 1 furtherincluding as components of said solution:a surface active component; anda chelating component.
 5. The ophthalmic solution of claim 4 whereinsaid chelating component is edetate disodium.
 6. The ophthalmic solutionof claim 4 wherein said surface active component is poloxamine or BAK.7. An ophthalmic solution useful as an artificial tear, consistingessentially of:polyvinylpyrrolidone in an amount of about 0.100%;benzalkonium chloride in an amount of about 0.010% by weight; andglycerin in an amount of about 0.200% by weight; wherein saidcomposition is an aqueous solution, having isotonic properties withrespect to an eye.
 8. The composition of claim 7 further including aneffective amount of edetate disodium as a co-preservative and chelatingagent, and an effective amount of potassium chloride and sodium chloridefor adjusting osmolality.
 9. A method of treating the eye for irritationor dryness, comprising contacting said eye with an ophthalmic solutionconsisting essentially of about 0.1 to 1.5% by weight ofpolyvinylpyrrolidone, sodium borate,/boric acid, about 0.01 to 0.10% byweight of an effective ophthalmic preservative, and about 0.2 to 1.0% byweight of glycerin, wherein said solution is an aqueous solution havingisotonic properties with respect to the eye, whereby the osmolality hasbeen adjusted with sodium chloride and potassium chloride.
 10. Themethod of claim 9 wherein said solution further comprises a preservativethat is BAK in an amount of 0.010% by weight.
 11. The method of claim 9wherein said preservative is BAK, sorbic acid, chlorobutanol, disodiumethylenediamine tetracetate, and/or polyquaternium-1 or acetamide.